Unsupervised Learning in Drug Design from Self-Organization to Deep Chemistry

The availability of computers has brought novel prospects in drug design. Neural networks (NN) were an early tool that cheminformatics tested for converting data into drugs. However, the initial interest faded for almost two decades. The recent success of Deep Learning (DL) has inspired a renaissance of neural networks for their potential application in deep chemistry. DL targets direct data analysis without any human intervention. Although back-propagation NN is the main algorithm in the DL that is currently being used, unsupervised learning can be even more efficient. We review self-organizing maps (SOM) in mapping molecular representations from the 1990s to the current deep chemistry. We discovered the enormous efficiency of SOM not only for features that could be expected by humans, but also for those that are not trivial to human chemists. We reviewed the DL projects in the current literature, especially unsupervised architectures. DL appears to be efficient in pattern recognition (Deep Face) or chess (Deep Blue). However, an efficient deep chemistry is still a matter for the future. This is because the availability of measured property data in chemistry is still limited

Objective models for steroid binding sites of human globulins

We report the application of a recently developed alignment-free 3D QSAR method [Crippen,G.M., J. Comput. Chem., 16 (1995) 486] to a benchmark-type problem. The test systeminvolves the binding of 31 steroid compounds to two kinds of human carrier protein. Themethod used not only allows for arbitrary binding modes, but also avoids the problems oftraditional least-squares techniques with regard to the implicit neglect of informative outlyingdata points. It is seen that models of considerable predictive power can be obtained even witha very vague binding site description. Underlining a systematic, but usually ignored, problemof the QSAR approach, there is not one unique type of model but, rather, an entire manifoldof distinctly different models that are all compatible with the experimental information. Fora given model, there is also a considerable variation in the found binding modes, illustratingthe problems that are inherent in the need for ’correct‘ molecular alignment in conventional3D QSAR methods.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42963/1/10822_2004_Article_199064.pd

Endogenous regulation of seasonal energetic phenotypes: investigating the hormonal mechanisms of fat gain and muscle growth across avian life-history stages in two Arctic birds

Animals living or breeding in highly seasonal temperate and polar ecosystems require stored energy (i.e. lipids and protein) in the form of somatic reserves to prepare for predictable energetically demanding stages within their annual cycle, such as hibernation, migration, reproduction, or overwintering. However, the physiological mechanisms underlying fat and muscle gain in free-living vertebrates are not fully known. Nonetheless, research in mammals and poultry have identified a number of energy-regulating hormones that mediate metabolic (peripheral) and behavioural (central) effects on lipid and protein stores. Here I extensively reviewed the mechanistic advances on energy-regulating hormones in birds, and then integrate concepts from mammalian studies to design a conceptual framework for field-testing in avian systems. To test this, I then used a comparative approach to examine the temporal and stage-related variation in circulating levels of fat- (baseline corticosterone) and muscle-promoting (testosterone and insulin-like growth factor-1 or IGF-1) hormones before spring migration in captive male snow buntings (Plectrophenax nivalis) and breeding in free-living female common eiders (Somateria mollissima). Baseline corticosterone did not appear to signal for fat deposition in premigratory buntings, while slight and rapid elevations in eiders may stimulate fattening and may fuel reproduction, respectively. Elevated testosterone in buntings may mediate skeletal muscle growth as the variation temporally matched muscle scores, where elevations in female eiders are potentially more important for breeding behaviours. In both species, the down-regulation of IGF-1 may represent a fat-sparing action, where the up-regulation may be for visceral organ remodeling. My results demonstrate potential for hormone pleiotropy on complex phenotypes, and my thesis collectively highlights the value of examining naturally circulating hormone levels as foundational information on phenotypic changes across a broad range of birds with stages in highly seasonal ecosystems

Glucocorticoids

As one class of the most important steroid hormones, glucocorticoids have long been recognised and their therapeutic benefits have been widely used in clinical treatment, especially in anti-inflammation cases. Glucocorticoids regulate various processes in the body including the mobilization of energy stores, immune functions, gene expression, and maintenance of the homeostasis as well as the stress response, this is not surprising that the concept of "glucocorticoids" is mentioned in almost all medical text books that focus on specific organs or systems such as the cardiovascular system, the immune system, and the neuroendocrine system. The book of Glucocorticoids - New Recognition of Our Familiar Friend aims to introduce the latest findings relating to glucocorticoids, either freshly from the laboratory or from clinical case studies, and to open up a new angle of looking at the issue of balancing the therapeutic benefits and side effects brought up by glucocorticoids

Functional and Material Properties in Nanocatalyst Design: A Data Handling and Sharing Problem

(1) Background: Properties and descriptors are two forms of molecular in silico representations. Properties can be further divided into functional, e.g., catalyst or drug activity, and material, e.g., X-ray crystal data. Millions of real measured functional property records are available for drugs or drug candidates in online databases. In contrast, there is not a single database that registers a real conversion, TON or TOF data for catalysts. All of the data are molecular descriptors or material properties, which are mainly of a calculation origin. (2) Results: Here, we explain the reason for this. We reviewed the data handling and sharing problems in the design and discovery of catalyst candidates particularly, material informatics and catalyst design, structural coding, data collection and validation, infrastructure for catalyst design and the online databases for catalyst design. (3) Conclusions: Material design requires a property prediction step. This can only be achieved based on the registered real property measurement. In reality, in catalyst design and discovery, we can observe either a severe functional property deficit or even property famine

Variation in the amphibian hypothalamic pituitary adrenal axis: Patterns, mechanisms, and implications

Many vertebrate stress responses are mediated by the hypothalamic-pituitary-adrenal/interrenal (HPA/I) axis, which involves hypothalamic secretion of corticotropin releasing factor (CRF) and increased plasma levels of glucocorticoid hormones (GCs) like corticosterone (CORT). Basal HPA/I activity is also imperative to maintaining homeostasis. Despite having crucial roles, HPA/I activity is variable and can be influenced by factors like environment, physiology, and life-history. HPA/I activity also influences reproduction and immunity. To better understand patterns of HPA/I variation (specifically CORT and CRF), we conducted several studies using plethodontid salamanders. Their low-energy lifestyle offers unique contrast to studies of stress physiology in high-energy animals like mammals and birds. Understanding amphibian stress physiology is also important because environmental stressors are linked to amphibian population declines. First, we sampled free-living Allegheny Mountain dusky salamanders (Desmognathus ochrophaeus) to identify physiological factors associated with CORT variation. White blood cells were the strongest predictors of HPA/I activity compared to reproductive investment, fat stores, or body condition. This indicated HPA/I activity is correlated with immunity and supported the facilitation hypothesis. Second, we investigated HPA/I variation in reproductive and nonreproductive female red-legged salamanders (Plethodon shermani) and found no evidence that reproductive condition influences HPA/I activity. Next, we tested the effects of CORT on immune function and wound healing in Allegheny Mountain dusky salamanders. Exogenous CORT elevation, but not a daily chasing stressor, delayed wound healing. This indicates that elevated CORT can delay healing, but endogenous elevation may be suppressed under natural conditions since a daily stressor did not suppress healing despite decreasing body mass and increasing mortality. Finally, we tested whether testosterone (T) suppressed healing as predicted by the immunocompetence handicap hypothesis and found no evidence that T affects healing in dusky salamanders, but a prior surgery enhanced healing of a subsequent induced wound. Together these studies highlight the relationship between HPA/I activity and immunity; whereas, we found no evidence that reproductive condition, fat stores, or body condition relate to HPA/I activity in plethodontid salamanders. This work has implications for understanding vertebrate stress physiology in general and for better understanding amphibian stress responses and how plasma GCs mediate these responses

The effects of endogenous and exogenous gonadal hormones on spatial navigation in women and in female rats.

Gonadal hormones, both endogenous and exogenous, are implicated in cognition. Yet, the role of gonadal hormones in spatial navigation remains relatively unexplored. While navigating a maze either place memory or response memory can be used. The gonadal hormone 17β-estradiol affects which memory system female rats use during navigation, thus producing a memory bias. Across the menstrual cycle, women's memory bias is also altered. This thesis examined the role of endogenous and exogenous hormones in spatial navigation in both female rats and in women. It was shown that the endogenous hormone, progesterone promoted the use of response memory in females. It was also shown that the exogenous hormones used in hormonal contraceptives impact memory bias in females. However, the impact of these hormones on spatial navigation was different in rats than what was observed in humans. It was also shown that both endogenous and exogenous hormones have different effects depending on whether they are administered alone or in combination. Both endogenous and exogenous gonadal hormones are involved in memory bias during spatial navigation in females

Prediction of protein-ligand binding affinity using neural networks

Master'sMASTER OF SCIENC

Différences sexuelles, androgènes et glucocorticoïdes dans le poumon foetal durant une période gestationnelle tardive qui chevauche la montée de la production du surfactant pulmonaire

Le syndrome de détresse respiratoire (SDR) est plus fréquent chez les nouveau-nés de sexe masculin que féminin, alors que les androgènes et les glucocorticoïdes sont reconnus pour ralentir et accélérer, respectivement, la maturation pulmonaire. Premièrement, nous avons étudié les différences sexuelles dans le transcriptome pulmonaire fœtal chez la souris par une approche de micropuces d’ADN durant une fenêtre de gestation qui précède et inclut la montée de production du surfactant, qui est asynchrone entre femelles et mâles en défaveur de ces derniers. Quatre-vingt-huit transcrits présentant une différence sexuelle dans leur niveau d’expression aux jours gestationnels (JG) 15.5, 16.5 ou 17.5 ont été identifiés. Ils sont impliqués notamment dans la régulation et le métabolisme hormonal, l’apoptose, la régulation transcriptionnelle et le métabolisme des lipides et sont des candidats pour un rôle dans la maturation pulmonaire et la physiopathologie du SDR. Deuxièmement, l’expression des 17β-hydroxystéroïdes déshydrogénases (17βHSD) de types 2 et 5, qui sont respectivement impliquées dans l’inactivation et la synthèse des androgènes, et du récepteur des androgènes (AR) a été caractérisée dans des poumons fœtaux humains. Des relations entre les niveaux d’expression et l’âge gestationnel ont été observées. La 17βHSD2 et le AR ont été co-localisés notamment dans l’épithélium, alors que la 17βHSD5 a été localisée dans certaines cellules épithéliales. Le niveau protéique de AR a montré d’importantes différences interindividuelles. Ces résultats supportent l’existence d’un métabolisme local des androgènes et une régulation fine de l’occupation de AR dans les poumons fœtaux mâles et femelles durant la période où une naissance prématurée présente de hauts risques. Troisièmement, l’expression de gènes associés à l’axe hypothalamo-hypophyso-surrénalien (HPA) a été quantifiée et localisée dans des poumons fœtaux murins aux JG 15.5, 16.5 et 17.5. La capacité de la corticolibérine (CRH) et de la corticotropine à stimuler l’expression d’enzymes de synthèse de glucocorticoïdes par le poumon fœtal a aussi été abordée, ainsi que la production de glucocorticoïdes. Différents profils d’expression ont été déterminés, l’incubation d’explants pulmonaires fœtaux en présence de CRH augmenta l’expression de la 21-hydroxylase, alors qu’une production de désoxycorticostérone a été détectée. Les modulations temporelles et spatiales observées suggèrent des rôles dans le développement pulmonaire pour des gènes associés à l’axe HPA.Respiratory distress syndrome (RDS) is more frequent in male neonates than female neonates. Androgens and glucocorticoids are known to delay and accelerate, respectively, the fetal lung maturation. Firstly, we studied the sex differences in the mouse fetal lung transcriptome during a gestational period that overlaps the surge of surfactant synthesis, which occurs earlier in females than in males. Using DNA microarrays, 88 transcripts showing a sex difference in expression at gestational days (GD) 15.5, 16.5, or 17.5 were identified. Those genes were associated to several functional categories, including hormone metabolism and regulation, apoptosis, transcriptional regulation, and lipid metabolism, and are candidates for roles in lung maturation and in the physiopathology of RDS. Secondly, the expression of 17β-hydroxysteroid dehydrogenases (17βHSD) type 2 and 5, which are respectively involved in androgen inactivation and synthesis, and of the androgen receptor (AR), was characterized in human fetal lungs. Statistically significant relationships between expression levels and gestational age were observed. In particular, 17βHSD2 and AR were co-localized in epithelial cells, while 17βHSD5 was localized in a subset of epithelial cells mostly in conducting zones. AR protein levels showed an important interindividual variability. The obtained results support the presence of a local androgen metabolism and a fine-tuning of AR occupancy in human male and female fetal lungs during a gestational period associated with high-risk premature birth. Thirdly, the expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes was quantified and localized in murine fetal lungs at GD 15.5, 16.5, and 17.5. Also, the capability of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) to stimulate the pulmonary expression of enzymes involved in the “adrenal” pathway of glucocorticoid synthesis was addressed, as well as the glucocorticoid production. Several distinct gene expression profiles were established, the incubation of fetal lung explants with CRH led to increased levels of 21-hydroxylase gene expression, whereas deoxycorticosterone accumulation was detected. The observed temporal and spatial modulations suggest roles for HPA axis-related genes in the developing lung